Adenylation Activity of Carboxylic Acid Reductases Enables the Synthesis of Amides. Issue 46 (11th October 2017)

• Record Type: Journal Article
• Authors: Wood, Alexander J. L.; Weise, Nicholas J.; Frampton, Joseph D.; Dunstan, Mark S.; Hollas, Michael A.; Derrington, Sasha R.; Lloyd, Richard C.; Quaglia, Daniela; Parmeggiani, Fabio; Leys, David; Turner, Nicholas J.; Flitsch, Sabine L.
• Is Part Of: Angewandte Chemie international edition. Volume 56:Issue 46(2017)
• Page Start: 14498
• Page End: 14501
• Publication Date: 2017-10-11
• Subjects: amidation -- amides -- amido synthetase -- biocatalysis -- carboxylic acid reductase; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201707918
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Carboxylic acid reductases (CARs) catalyze the reduction of a broad range of carboxylic acids to aldehydes using the cofactors adenosine triphosphate and nicotinamide adenine dinucleotide phosphate, and have become attractive biocatalysts for organic synthesis. Mechanistic understanding of CARs was used to expand reaction scope, generating biocatalysts for amide bond formation from carboxylic acid and amine. CARs demonstrated amidation activity for various acids and amines. Optimization of reaction conditions, with respect to pH and temperature, allowed for the synthesis of the anticonvulsant ilepcimide with up to 96 % conversion. Mechanistic studies using site‐directed mutagenesis suggest that, following initial enzymatic adenylation of substrates, amidation of the carboxylic acid proceeds by direct reaction of the acyl adenylate with amine nucleophiles. Abstract : CARpe diem : Carboxylic acid reductases can be used as biocatalysts for the activation and subsequent amidation of a range of carboxylic acids with primary and secondary amines, as well as ammonia. The enzymes were used to synthesize the anticonvulsant ilepcimide. Key: adenosine triphosphate (ATP), nicotinamide adenine dinucleotide phosphate (NADPH).